UKPID MONOGRAPH COBALT SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH This monograph has been produced by staff of a National Poisons Information Service Centre in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Peer review group: Directors of the UK National Poisons Information Service. COBALT Toxbase summary Type of product Used in alloys, magnets, in the production of tungsten carbide, in catalysts, pigments and enamels. Toxicity Cobalt and its salts are relatively non toxic by ingestion. Most cases of cobalt toxicity relate to occupational skin contact or inhalation. Features Topical - Cobalt is a topical irritant and a well recognised cause of occupational contact dermatitis. - Cobalt sensitivity may be the cause of metal prosthesis failure. - Simultaneous allergies to nickel and cobalt are frequent. - Orofacial granulomatosis has been described in association with delayed cobalt hypersensitivity. Ingestion - Nausea, vomiting, abdominal pain. A transient neutropenia occurred in a six year old child who ingested 2.5 g cobalt chloride. - Congestive cardiomyopathy has been reported after the consumption of large quantities of beer to which cobalt had been added as a foam stabiliser and in those receiving oral cobalt therapy in the treatment of anaemia. Inhalation - Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal (tungsten carbide) industry. Symptoms usually arise after several years and may manifest as pneumoconiosis (with dyspnoea and cough secondary to interstitial fibrosis), an allergic alveolitis or occupational asthma. - Corpulmonale may complicate hard metal pneumoconiosis. - There are occasional reports of cobalt cardiomyopathy following occupational exposure. Management Topical - Removal from exposure is the priority. Remember the cobalt source may not be immediately apparent e.g. in prostheses. Ingestion 1. Supportive care only. Replace fluids and electrolytes as necessary. 2. Gastrointestinal decontamination is not necessary. 3. Check the full blood count. 4. If chronic cobalt ingestion is suspected consider the possibility of cobalt cardiomyopathy and check thyroid function to exclude hypothyroidism. 5. Collect blood and urine for cobalt concentration determination in symptomatic patients. Cobalt assays are not widely available. Check with NPIS. Inhalation Acute inhalation: 1. Remove from exposure and treat symptomatically. Chronic inhalation: 1. Asthmatic symptoms respond to conventional measures. 2. Established pulmonary fibrosis generally has a poor prognosis. Cyclophosphamide may have a role but seek specialist advice from the NPIS. References Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty- eight cases. Am J Med 1972; 53: 395-417. Cugell DW. The hard metal diseases. Clin Chest Med 1992; 13: 269-79. Curtis JR, Goode GC, Herrington J, Urdaneta LE. Possible cobalt toxicity in maintenance hemodialysis patients after treatment with cobaltous chloride: a study of blood and tissue cobalt concentrations in normal subjects and patients with terminal renal failure. Clin Nephrol 1976; 5: 61-5. Manifold IH, Platts MM, Kennedy A. Cobalt cardiomyopathy in a patient on maintenance haemodialysis. BMJ 1978; 2: 1609. Mucklow ES, Griffin SJ, Delves HT, Suchak B. Cobalt poisoning in a 6-year-old. Lancet 1990; 335: 981. Pryce DW, King CM. Orofacial granulomatosis associated with delayed hypersensitivity to cobalt. Clin Exp Dermatol 1990; 15: 384-6. Sullivan JF, Egan JD, George RP. A distinctive myocardiopathy occurring in Omaha, Nebraska: clinical aspects. Ann NY Acad Sci 1969; 156: 526-43. Substance name Cobalt Origin of substance Naturally occurring in ores. (DOSE, 1993) Synonyms Aquacat Super cobalt Cobalt-59 (DOSE, 1993) Chemical group A transition metal (d block) element Reference numbers CAS 7440-48-4 (DOSE, 1993 RTECS GF8750000 (RTECS, 1996) UN NIF HAZCHEM CODE NIF Physico-chemical properties Chemical structure Cobalt, Co (DOSE, 1993) Molecular weight 58.93 (DOSE, 1993) Physical state at room temperature Solid Colour Silvery-grey (HSDB, 1996) Odour Odourless (HSDB, 1996) Viscosity NA pH NA Solubility Solubility in water:<1 mg/ml at 19°C. (DOSE, 1993) Soluble in dimethyl sulphide, ethanol and acetone. (HSDB, 1996) Autoignition temperature NIF Chemical interactions Contact of cobalt dust with strong oxidizers may cause fire and explosions. Cobalt will react violently and sometimes explosively with fused ammonium nitrate. (HSDB, 1996) At ambient or slightly elevated temperatures cobalt powder will react violently with bromine pentafluoride, ignition often occurring. (NFPA, 1986) Pyrophoric cobalt decomposes acetylene in cold and becomes incandescent. (NFPA, 1986) Glowing or white incandescence occurs when nitryl fluoride is passed over cobalt at mild warming temperatures. (HSDB, 1996) Major products of combustion NIF Explosive limits NA Flammability Fire potential moderate when exposed to heat of flame. (HSDB, 1996) Boiling point 2870°C (DOSE, 1993) Density 8.92 at 20°C (DOSE, 1993) Vapour pressure 0 Pa at 20°C (HSDB, 1996) Relative vapour density NA Flash Point NA Reactivity NIF Uses Cobalt is used widely as an alloying ingredient together with nickel, chromium, molybdenum and other elements. These alloys are utilised in jet aircraft, gas turbines and other equipment operating at high temperatures. Cobalt is an important constituent of magnets. Cobalt is the binder employed in the production of tungsten carbide which, due to its toughness and shock resistance, is used in drill bits and machine tools. 60Co, the artificially produced radioisotope is sometimes used in place of x-rays to inspect the internal structure of materials. Cobalt oxide is used in the glass and ceramic industries as a pigment, and for enamelling purposes. Cobalt catalysts are used in many industrial reactions; cobalt hydrocarbonyl may be used as a catalyst in organic reactions. (PATTY, 1994) Hazard/risk classification Index no. 027-001-00-9 Risk phrases R42/43 - May cause sensitisation by inhalation and skin contact. Safety phrases Xn; S(2-)22-24-37 - Harmful. Keep out of reach of children. Do not breathe dust. Avoid contact with the skin. Wear suitable gloves. EEC no. 231-158-0 (CHIP2, 1994) INTRODUCTION Cobalt is a relatively rare element that usually exists in association with nickel, silver, lead, copper and iron ores. Occupational exposure to cobalt dust occurs mainly in the tungsten carbide industry but has been reported also in diamond polishers (Lahaye et al, 1984) and dental technicians (Sherson et al, 1990). It is an essential dietary trace element as a component of vitamin B12 (cyanocobalamin), each molecule of the vitamin containing one atom of cobalt. Cigarettes contain cobalt but most of this is in the paper of the butt which contains approximately 4 µg cobalt compared to 0.4 µg in the cigarette. Linnainmaa and Kiilunen (1997) estimated that the butt paper cobalt from 100 cigarettes would need to be absorbed to achieve cobalt uptake equivalent to eight hours exposure to 0.05 mgCo/m3. MECHANISM OF TOXICITY Cobalt interacts with sulphydryl groups to impair thiol-enzyme activities (Alexander, 1972). In in-vitro studies cobalt causes DNA damage and induces the formation of reactive oxygen species in the presence of hydrogen peroxide (Beyersman and Hartwig, 1992). Cobalt is immunogenic and may act as a hapten in the induction of bronchial and dermal hypersensitivity (Sjögren et al, 1980). Evidence for an autoimmune mechanism in hard-metal lung disease is suggested by the recurrence of disease in a single transplanted lung despite no evidence of cobalt in the donated organ (Frost et al, 1993). In a dog model cobalt myocardial toxicity was characterized by vacuolation and loss of myofibers (Sandusky et al, 1981a) with histochemical evidence of severe mitochondrial damage (Sandusky et al, 1981b). This is probably related to cobalt-thiol group interaction causing citric acid cycle malfunction (Jarvis et al, 1992). The erythropoietic effect of cobalt is attributed to increased erythropoietin release from damaged renal cells (Alexander, 1972). In cobalt pneumoconiosis non-respiratory symptoms of constitutional upset are thought to be due to the release of a tumour necrosis factor (Rolfe et al, 1992). TOXICOKINETICS Absorption Cobalt can be absorbed orally, by inhalation and dermal exposure (Domingo, 1989; Scansetti et al, 1994). Cobalt and iron share the same transport mechanism within the small intestine such that cobalt ingestion competitively inhibits iron uptake. The extent of intestinal cobalt absorption after ingestion depends on the dose with only some 20 per cent of a large ingestion being absorbed (Domingo, 1989). Some inhaled cobalt undergoes mucociliary clearance while particles which reach the distant pulmonary tree are taken up predominantly by macrophages (Evans et al, 1993). Distribution The normal body burden of cobalt is about 1.1 mg. Approximately 43 per cent is in muscle with some 14 per cent in bone and the remainder in other soft tissues (Domingo, 1989). Excretion Cobalt which reaches the systemic circulation is eliminated predominantly in urine with a variable but small amount excreted in bile (Domingo, 1989). Following acute occupational cobalt exposure the urinary elimination of cobalt is rapid for the first 24 hours followed by a slower excretion phase lasting several weeks (Alexandersson, 1988). A small proportion of retained cobalt has a biological half-life of several years (Elinder and Friberg, 1986). CLINICAL FEATURES: ACUTE EXPOSURE Ingestion Cobalt salts are relatively non-toxic but ingestion may lead to gastrointestinal and rarely transient haematological disturbance (see below). Gastrointestinal toxicity A six year-old boy developed nausea and vomiting after swallowing a drink to which he had added about 2.5 g cobalt chloride from a crystal growing set (Mucklow et al, 1990). The serum cobalt concentration some seven hours post ingestion was 434 µg/L (normal range <1 µg/L) but he made a full recovery. Everson et al (1988) reported a 14 year-old female who vomited but was otherwise asymptomatic following ingestion of a small (undetermined) amount of cobalt chloride from her brother's chemistry set. The serum cobalt concentration 12 hours post ingestion was 78 µg/L. Haemotoxicity A six year old boy who ingested 2.5 g cobalt chloride (Mucklow et al 1990) developed a transient neutropenia (1.7 x 109/L) but recovered fully. CLINICAL FEATURES: CHRONIC EXPOSURE Dermal exposure Cobalt is a topical irritant (Fischer and Rystedt, 1985) and a well recognised cause of occupational contact dermatitis which has been described in hard metal workers (Cugell, 1992), printers, builders (Kiec-Swierczynska, 1990; Irvine et al, 1994) and employees in the rubber (Foussereau and Cavelier, 1988) and glass-fibre-reinforced plastics (Tarvainen et al, 1993) industries. Cobalt sensitivity may also be caused by exposure to jewellery, metal buttons, plastics and domestic detergents (Castiglioni et al, 1992). Photosensitization to cobalt has been reported (Camarasa and Alomar, 1981; Manciet et al, 1995). Cobalt contact allergy is an important cause of metal prosthesis failure with joint loosening and dislocation, local bone resorption and fractures (Jones et al, 1975). There may be an associated dermatitis which can spread beyond the primary irritation site (Merle et al, 1992). A widespread allergic vasculitis due to cobalt sensitivity from a cobalt alloy prosthesis has also been described (Munrow-Ashman and Miller, 1976). Dental prostheses containing cobalt also have caused local irritation with gingivitis and stomatitis in addition to a remote dermatitis (Hildebrand et al, 1989). A 56 year-old woman developed intense pain and burning of the lips, with oedema and erosive lesions following implantation of a dental prosthesis in the superior dental arch. The prosthesis was mainly composed of a methylacrylate containing cobalt, chromium and nickel. A series of patch tests revealed an isolated strong positivity for cobalt chloride. This was the first report in which hypersensitivity to cobalt in a dental prosthesis was suggested as a possible cause of erosive oral lichen planus (Torresani et al, 1994). Simultaneous allergies to nickel and cobalt are frequent (Burden and Eedy, 1991) and there is some evidence for a mutual enhancing effect of contact sensitization to one metal in the presence of the other (Domingo, 1989). The administration of disulfiram in the treatment of ethanol abuse has led to an exacerbation of cobalt dermatitis presumably via diethyldithiocarbamate (a disulfiram metabolite) chelation and mobilization of cobalt in a manner similar to that reported in nickel sensitive subjects (Menné, 1985). Pryce and King (1990) described a patient with orofacial granulomatosis in association with delayed cobalt hypersensitivity suggesting that this condition is allergy - based. The source of cobalt was traced to plastic pens and crayons which the patient sucked frequently. Tattoos containing cobalt have also initiated a granulomatous reaction (Ro and Lee, 1991). Ingestion Gastrointestinal toxicity Gastrointestinal symptoms similar to those occurring after acute cobalt salt ingestion have also complicated chronic therapy. A 35 year-old woman with anaemia treated with cobalt chloride 25 mg qds complained of nausea, vomiting and weight loss in addition to the neurological symptoms described below (Schirrmacher, 1967). Cardiovascular toxicity Congestive cardiomyopathy has been reported in people who drank large quantities of beer to which cobalt had been added as a foam stabilizer (Morin et al, 1967; Kesteloot et al, 1968; Sullivan et al, 1969) and in those receiving oral cobalt therapy (Manifold et al, 1978). In a study of 28 cases of cobalt beer cardiomyopathy (Alexander, 1972) symptoms of cardiac failure were of fairly abrupt onset (mean duration at presentation 10 weeks) and variable severity with five deaths from cardiogenic shock and a full physical recovery in only 11 patients. Cardiomegaly, a pericardial effusion and polycythemia were present in the majority with pleural effusion in 11 cases though radiological evidence of pulmonary oedema "characteristically ..... was absent". Profound lactic acidosis was a prominent feature in severe cases. Electrocardiographic abnormalities included p pulmonale or p mitrale, axis (usually right) deviation and acute ischaemic changes in the precordial leads typically associated with raised plasma cardiac enzyme concentrations. Electron microscopy of myocardial tissue from these patients showed extensive myofibril degeneration with abnormal mitochondria containing electron-dense bodies believed to incorporate cobalt. It is probable that alcohol and malnutrition contributed to the cardiotoxicity observed in these and other cases since the absolute quantities of cobalt ingested often were small (up to 10 mg daily) (Kesteloot et al, 1968; Alexander, 1972). Curtis et al (1976) described a haemodialysis patient who died three months after "a course" of cobalt chloride. At post mortem the myocardial cobalt concentration was 1.65 µg/g, some 25-80 times greater than myocardial cobalt concentrations in haemodialysis patients who had not received cobalt. These authors noted that renal failure haemodialysis patients treated with oral cobalt chloride had significantly higher (p=0.001) blood cobalt concentrations than patients who had not received cobalt thus identifying renal failure patients as an 'at risk' group for cobalt toxicity (see below). In another report a 17 year-old girl on maintenance haemodialysis died from rapidly progressive dilated cardiomyopathy after nine months cobalt chloride therapy (25 mg bd) for anaemia. At necropsy the myocardial cobalt concentration was 8.9 µg/g (Manifold et al, 1978). Neurotoxicity After six months treatment with cobalt-chloride 25 mg qds for anaemia a 35 year-old woman developed limb paraesthesiae, an unsteady gait, impaired hearing and dizzy spells in addition to nausea, vomiting and weight loss (Schirrmacher, 1967). Clinical examination confirmed bilateral nerve deafness, absent ankle reflexes and impaired vibration sense which all resolved with four months of cobalt withdrawal. Haemotoxicity Chronic ingestion of excess cobalt causes polycythaemia which in the past led to its use in the treatment of anaemia (Manifold et al, 1978). A 13 month-old child developed persistent anaemia with polycythaemia and cardiomegaly in addition to hypothyroidism (see below) and hypertrichosis following treatment of iron deficiency for one year with a commercial iron-cobalt preparation. At the end of the treatment period the serum cobalt concentration was 59 µg/L. The haematological abnormalities and hypothyroidism resolved when the treatment was stopped, with some improvement in cardiac size and a fall in the serum cobalt concentration to 6.8 µg/L and 1.4 µg/L at four and 12 months respectively (Bianchi et al, 1989). Endocrine toxicity Cobalt inhibits the iodination of tyrosine and goitre is a recognised side-effect of cobalt therapy (Schirrmacher, 1967). A 13 month-old baby developed clinical and biochemical hypothyroidism after treatment of iron deficiency for one year with a commercial iron-cobalt preparation. The endocrine abnormality resolved when treatment was withdrawn (Bianchi et al, 1989). Ocular toxicity Following treatment of pancytopenia with 73 g oral cobalt chloride over two and a half years, a patient developed abnormal choroidal perfusion and optic atrophy. Vision did not deteriorate further following cessation of therapy (Licht et al, 1972). Inhalation Pulmonary toxicity Pulmonary toxicity following chronic cobalt exposure is associated typically with the hard metal (tungsten carbide in a cobalt matrix) industry (Auchincloss et al, 1992) but similar problems have been reported in diamond polishers using cobalt-coated discs (Lahaye et al, 1984; Nemery et al, 1990) and in a dental technician (Sherson et al, 1990). Lung disease in the hard metal industry is more common among workers exposed to ionized cobalt (dissolved in machine coolants) than in those exposed to dry (non-ionized) cobalt dusts even though the dust-exposed group usually work in the highest ambient air cobalt concentrations (Cugell, 1992). There is some debate concerning whether cobalt exposure alone is sufficient to cause pulmonary fibrosis. In-vitro and animal studies suggest there is no relationship between cellular cobalt uptake and cellular toxicity (Lison and Lauwerys, 1994) and cobalt workers frequently are exposed to several other potential toxins (including tungsten carbide, iron, silica and diamond) (Swennen et al, 1993). While Gennart and Lauwerys (1990) observed a significantly increased incidence (p<0.05) of restrictive spirometry and respiratory symptoms in workers exposed for more than five years to cobalt dust in a plant producing diamond-cobalt circular saws compared to non cobalt-exposed factory workers, Swennen et al (1993) found no difference in ventilatory performance, lung volumes or carbon monoxide diffusion capacity between 82 cobalt refinery workers and controls even though the cobalt workers complained more frequently of wheeze and dyspnoea. Hard metal pneumoconiosis Chronic cobalt (and tungsten carbide) inhalation is associated typically with "hard metal" pneumoconiosis characterized by interstitial fibrosis (primarily of the lower zones) and a restrictive ventilatory defect. Patients usually present with exertional dyspnoea, cough and sometimes chest tightness (Bech et al, 1962). There may be associated constitutional symptoms of fever, weight loss or general malaise (Coates and Watson, 1971; Balmes, 1987; Migliori et al, 1994). In one study of 12 tungsten carbide workers the mean duration of exposure before the onset of respiratory symptoms was 12 years with a range of 1 month to 28 years (Coates and Watson, 1971). Inspiratory crackles are the earliest physical sign (Rochat et al, 1987) but finger clubbing, cyanosis and eventually corpulmonale may ensue. Chest x-ray findings vary greatly (Cugell et al, 1990) but usually show increased linear markings and small nodular opacities in the lower (and mid) zones with later cardiomegaly and features of pulmonary hypertension (Bech et al, 1962). Many patients develop a form of pulmonary fibrosis complicated by atypical intraalveolar giant cells (Davison et al, 1983; Rochat et al, 1987; Cugell, 1992) which can be demonstrated in bronchoalveolar lavage fluid (Forni, 1994). Forni (1994) suggested that a persistently high bronchoalveolar lavage eosinophil count despite steroid therapy and cessation of exposure carried an unfavourable prognosis in patients with hard metal lung disease. Several fatalities from hard metal pneumoconiosis have been reported (Della-Torre et al, 1990; Figueroa et al, 1992). Nemery et al (1990) described a 52 year-old diamond polisher who died less than one year after a diagnosis of interstitial lung disease. He continued work without specific treatment until three months before death when he required continuous oxygen and systemic steroids. At autopsy there was evidence of extensive fibrosis with interstitial giant cells. The lung cobalt concentration was 2.1 µg/g. The authors suggested that oxygen therapy may have exacerbated this man's deterioration via cobalt-induced hydroxyl free radical formation. Allergic alveolitis An allergic alveolitis has been described in hard-metal workers with cough, dyspnoea and flu-like symptoms associated with bilateral crackles, radiographic small nodular infiltrates and a restrictive lung function defect (Sjögren et al, 1980; Cugell, 1992). These abnormalities may reverse if exposure ceases but with continued cobalt inhalation irreversible fibrosis is likely (Cugell, 1992). Occupational asthma Hard metal workers may develop occupational asthma with cough, wheeze and dyspnoea that characteristically improves during week-ends and holidays (Sprince et al, 1988; Cugell, 1992). Similar symptoms have been described in diamond workers exposed to cobalt in polishing discs (Gheysens et al, 1985). In a study of 703 hard metal workers Kusaka et al (1996a) identified age (>40 years), atopy and cobalt exposure as risk factors for asthma. Surprisingly, low airborne cobalt concentrations (below 50 µg/m3) posed a greater risk of hard metal asthma than did higher air cobalt concentrations (Kusaka et al, 1996a) although the observed deterioration in ventilatory function seemed to be related to duration of cobalt exposure (Kusaka et al, 1996b). There was no significant difference in asthma prevalence between those exposed to the elemental (dust) or ionised (mist) metal (Kusaka et al, 1996a). Cobalt asthma is associated in some, but not all, cases with circulating cobalt-specific IgE and generalised bronchial hyperresponsiveness (Coates and Watson 1971; Sjögren et al, 1980; Kusaka et al, 1989; Shirakawa et al, 1989; Cugell, 1992). Respiratory cross-reactivity between cobalt and nickel has also been described (Shirakawa et al, 1990). Cardiovascular toxicity Patients with fulminant hard metal pneumoconiosis may, after several years, develop cor pulmonale with clinical and radiographic features of pulmonary hypertension and right heart failure (Bech et al, 1962). Cobalt cardiomyopathy is most frequently associated with chronic excess cobalt ingestion (see above) but an identical syndrome has been reported occasionally in those occupationally exposed (Barborik et al, 1972; Jarvis et al, 1992). Kennedy et al (1981) reported fatal cardiogenic shock in a 48 year-old hard metal worker following routine vagotomy and pyloroplasty for duodenal ulceration. The patient, who had handled tungsten carbide and cobalt dust for four years, initially developed signs of cardiovascular compromise during the operation and gradually deteriorated without evidence of ischaemic heart disease. At post-mortem the heart was dilated with extensive myocardial fibrosis and a myocardial cobalt concentration of 7 µg/g (normal range 0.1-0.4). Neurotoxicity Jordan et al (1990) reported significantly impaired attention (p<0.05) and verbal (p<0.001) memory in 12 hard metal workers exposed to tungsten carbide and cobalt (as dust and dissolved in an organic solvent) compared to healthy unexposed controls. However, all members of the study group had "pulmonary manifestations" of hard metal disease which may have affected performance. A patient occupational exposed (mainly via inhalation) to cobalt dust for 20 months developed bilateral optic atrophy and bilateral nerve deafness. Fourteen months after stopping work visual activity improved and hearing returned to normal (Meecham and Humphrey, 1991). Nephrotoxicity Lechleitner et al (1993) reported Goodpasture's syndrome in a 26 year-old hard metal worker with severe interstitial lung disease and fulminant glomerulonephritis. The role of heavy metal exposure in the aetiology of this case is not known though the authors proposed cobalt-induced ß-cell activation or exposure of pulmonary basement membrane antigens as possible disease mechanisms. MANAGEMENT Dermal exposure Removal from exposure is the priority. It is important to remember that the cobalt source may not be immediately apparent, for example, when in a dental or other prosthesis. The role of chelation therapy in cobalt contact sensitivity is discussed below. Inhalation Removal from exposure is the principle requirement. The possibility of cobalt cardiotoxicity should be remembered in those in whom exposure is chronic. Asthmatic symptoms respond to conventional measures (Pisati and Zedda, 1994). Established pulmonary fibrosis has a generally poor prognosis although there are reports of substantial improvement following removal from the workplace (Zanelli et al, 1994). The role of blood and urine cobalt concentration measurements is discussed below (Medical Surveillance). Ingestion Decontamination Gastric lavage is unnecessary as cobalt ingestion produces only low acute oral toxicity and there is no evidence that oral activated charcoal reduces gastrointestinal cobalt absorption. Supportive measures Following acute cobalt salt ingestion supportive care is usually all that is required with intravenous fluid replacement if vomiting is severe. Plasma creatinine, urea and electrolytes and full blood count should be measured. If chronic cobalt toxicity is suspected a thorough cardiovascular and neurological (including fundoscopy) assessment should be undertaken. Thyroid function tests should be performed. The role of chelation therapy is discussed below (Antidotes). The presence of cobalt in blood and urine confirms exposure but blood and urine concentrations require careful interpretation (see Medical Surveillance) and these assays are not widely available. Antidotes DMSA Aposhian (1983) reported early animal studies published in the Chinese literature in 1965 which showed that DMSA (4 mmol/kg, route not stated) increased the LD50 of cobalt chloride-poisoned mice some three times. Four of ten mice administered 1.8 mmol/kg intraperitoneal cobalt chloride (a dose exceeding the LD95 immediately followed by intraperitoneal DMSA 3.4 mmol/kg survived two weeks (Llobet et al, 1986). Under these experimental conditions DMSA was a less effective cobalt chelator than calcium EDTA or DTPA (diethylenetriamine- pentacetic acid) (see below). DTPA Llobet et al (1986) reported a 70 per cent two week survival rate in mice administered intraperitoneal DTPA (3.1 mmol/kg) immediately following intraperitoneal loading with 1.8 mmol/kg cobalt chloride (a dose in excess of the LD95). Calcium EDTA All mice administered intraperitoneal cobalt chloride at doses approximating to the LD50-LD95 (0.6-1.8 mmol/kg), immediately followed by 4.3 mmol/kg intraperitoneal calcium EDTA (ethylenediamine tetraacetic acid) survived two weeks with significantly increased urine cobalt elimination in the 24 hours post antidote administration (Llobet et al, 1986). Allenby and Basketter (1989) found that a positive patch test reaction to one per cent aqueous cobalt chloride was abolished in five out of six subjects by the concomitant application of an equimolar EDTA solution. No cobalt was recovered in the urine of a patient with cobalt cardiomyopathy who received a one week course of calcium EDTA (and penicillamine, doses not stated) but treatment was not instituted until three years after cobalt ingestion (quantity not stated) (Alexander, 1972). The use of topical EDTA in cobalt dermatitis is discussed above (dermal exposure). Chemotherapy Balmes (1987) reported a 28 year-old lady with aggressive hard metal pneumoconiosis unresponsive to prednisolone (40-60 mg daily) who clinically improved significantly after two months of low-dose (25 mg bd) cyclophosphamide therapy. Haemodialysis In a patient with uraemic cardiomyopathy and a high serum cobalt concentration (0.24 ppb), Lins and Pehrsson (1976) reported reduced cardiac size in association with a fall in the serum cobalt concentration to 0.07 ppb during haemodialysis. However no cobalt dialysis clearance data or details of dialysis duration were given. AT RISK GROUPS Patients with renal failure are at risk of cobalt toxicity if administered oral cobalt containing pharmaceuticals (Curtis et al, 1976); these preparations are not available in the UK. MEDICAL SURVEILLANCE Regular monitoring of workplace airborne cobalt concentrations (Sala et al, 1994), strict attention to personal hygiene (Scansetti et al, 1994) and periodic assessment for pulmonary or dermatological symptoms are important in the prevention of cobalt toxicity. The recommended maximum exposure limit (eight-hour time weighted average 1995) in the UK for cobalt is 0.1 mg/m3 (Health and Safety Executive, 1995). Some studies suggest that airborne cobalt concentrations are frequently underestimated (Auchincloss et al, 1992; Mosconi et al, 1994) and other workers recently have reported average cobalt airborne concentrations in a hard metal factory greatly exceeding the recommended occupational exposure limit (Kumagai et al, 1996). Furthermore, significant reductions in FEV1 and FVC have been observed in workers exposed to airborne cobalt concentrations lower than 50 µg/m3 (Nemery et al, 1992). Sjögren et al (1980) noted that the development of cobalt contact dermatitis often preceded pulmonary disease and suggested that those with a positive cobalt patch test should be removed immediately from exposure. However, in another study only two of nine hard metal workers sensitive to inhaled cobalt had a positive cobalt patch test (Kusaka et al, 1986). Abnormal clinical findings should be investigated conventionally with particular attention to establishing a temporal relationship to workplace exposure in those with possible occupational asthma or alveolitis. The presence of cobalt-specific IgE in plasma or cobalt particles in bronchoalveolar lavage fluid or lung biopsy tissue may be useful. Increased blood and urine cobalt concentrations are frequently encountered in hard metal workers (Ichikawa et al, 1985; Stebbins et al, 1992) but are more useful as grouped rather than individual data (Sabbioni et al, 1994) and their significance requires careful interpretation. In workers exposed to cobalt dust in a plant producing diamond-cobalt saws urine cobalt concentrations reflected recent rather than cumulative cobalt exposure (Gennart and Lauwerys, 1990). Lison et al (1994) concluded that while urine and blood cobalt concentrations correlate reasonably well with recent exposure to soluble forms of cobalt (as in hard metal powders) the same is not true following exposure to insoluble cobalt oxide. No evidence of hard a metal pneumoconiosis or significantly excess heart disease was found in controlled study of 49 workers exposed to cobalt and cobalt oxides despite the presence of high urine cobalt concentrations (mean 340 g/L) (Morgan, 1983). OCCUPATIONAL DATA Maximum exposure limit Long-term exposure limit (8 hour TWA reference period) 0.1 mg/m3 (Health and Safety Executive, 1995). OTHER TOXICOLOGICAL DATA Carcinogenicity Animal studies suggest cobalt and its compounds are carcinogenic. While several studies have confirmed that hard metal workers exhibit excess lung cancer mortality, there is no strong evidence that cobalt or its compounds are carcinogenic in man (IARC, 1991). Assessment of human cancer risk is often confounded by simultaneous tobacco consumption, exposure to nickel and arsenic and small study population numbers (Mur et al, 1987; Jensen and Tüchsen, 1990). Mur et al (1987) observed an excess mortality form lung cancer (standardized mortality ratio = 4.66) in 1143 workers employed between 1950-1980 in a cobalt and sodium producing plant; smoking habits in the study population were not assessed. Further follow-up from 1981-88 failed to show a relationship between lung cancer and cobalt exposure (Moulin et al, 1993). Lasfargues et al (1994) reported a significantly higher mortality from lung cancer among 709 hard metal workers (employed for at least one year) compared to controls, though the study was too small to be conclusive. Reprotoxicity There is no conclusive evidence regarding the reprotoxicity of cobalt (Reprotox, 1996). Ratto et al, (1988) reported a successful pregnancy in a 31 year-old woman despite severe cobalt pneumoconiosis requiring systemic steroids and cyclophosphamide. Genotoxicity Salmonella typhimurium TA98, TA102, TA1535, TA1537 with metabolic activation negative; TA98, TA1537 without metabolic activation positive. Induced DNA strand breaks in human diploid fibroblasts and Chinese hamster ovary cells in vitro. In vivo rats 0.005 mg/kg cobalt metal in drinking water caused no mutagenic effects (DOSE, 1993). Fish toxicity LC50 (96 hr) fathead minnow 92 mg/L Rainbow trout tolerated 7 day exposure to 30 mg (Co)/L. Lethal limit 35 mg (Co)/L (DOSE, 1993). EC Directive on Drinking Water Quality 80/778/EEC NIF AUTHORS SM Bradberry BSc MB MRCP ST Beer BSc JA Vale MD FRCP FRCPE FRCPG FFOM National Poisons Information Service (Birmingham Centre), West Midlands Poisons Unit, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH UK This monograph was produced by the staff of the Birmingham Centre of the National Poisons Information Service in the United Kingdom. The work was commissioned and funded by the UK Departments of Health, and was designed as a source of detailed information for use by poisons information centres. Date of last revision 16/7/96 REFERENCES Alexander CS. Cobalt-beer cardiomyopathy. A clinical and pathologic study of twenty-eight cases. Am J Med 1972; 53: 395-417. Alexandersson R. Blood and urinary concentration as estimators of cobalt exposure. 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